极光激酶 A 使 p73 失活，从而抑制 DNA 损伤诱导的细胞凋亡和纺锤体组装检查点反应功能。
Aurora kinase-A inactivates DNA damage-induced apoptosis and spindle assembly checkpoint response functions of p73.
机构信息
Department of Molecular Pathology, The University of Texas M.D. Anderson Cancer Center, Houston, TX 77054, USA.
出版信息
Cancer Cell. 2012 Feb 14;21(2):196-211. doi: 10.1016/j.ccr.2011.12.025.
Abstract
Elevated Aurora kinase-A expression is correlated with abrogation of DNA damage-induced apoptotic response and mitotic spindle assembly checkpoint (SAC) override in human tumor cells. We report that Aurora-A phosphorylation of p73 at serine235 abrogates its transactivation function and causes cytoplasmic sequestration in a complex with the chaperon protein mortalin. Aurora-A phosphorylated p73 also facilitates inactivation of SAC through dissociation of the MAD2-CDC20 complex in cells undergoing mitosis. Cells expressing phosphor-mimetic mutant (S235D) of p73 manifest altered growth properties, resistance to cisplatin- induced apoptosis, as well as premature dissociation of the MAD2-CDC20 complex, and accelerated mitotic exit with SAC override in the presence of spindle damage. Elevated cytoplasmic p73 in Aurora-A overexpressing primary human tumors corroborates the experimental findings.
摘要
极光激酶-A 表达水平升高与人类肿瘤细胞中 DNA 损伤诱导的凋亡反应和有丝分裂纺锤体装配检查点 (SAC) 失控的消除有关。我们发现极光激酶-A 可使 p73 的丝氨酸 235 磷酸化，从而使其转录激活功能丧失，并与伴侣蛋白 mortalin 形成复合物而发生细胞质隔离。在有丝分裂的细胞中，极光激酶-A 磷酸化的 p73 还可通过 MAD2-CDC20 复合物的解离来促进 SAC 的失活。表达磷酸化模拟突变体（S235D）的 p73 的细胞表现出改变的生长特性、对顺铂诱导的凋亡的抗性，以及 MAD2-CDC20 复合物的过早解离，并在纺锤体损伤的情况下加速有丝分裂的退出和 SAC 失控。在过度表达极光激酶-A 的原发性人肿瘤中，细胞质内 p73 水平升高证实了这些实验结果。
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